Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research` Rury R. Holman, MB, ChB, FRCP Professor of Diabetic Medicine Director, Diabetes Trials Unit, Oxford Robert M. Califf, MD, MACC Vice Chancellor for Clinical Research Donald F. Fortin Professor of Cardiology, Duke University Director, Duke Translational Medicine Institute For the NAVIGATOR Study Group

NAVIGATOR Trial Organization Sponsored by Novartis Pharmaceuticals Executive Committee Trial Oversight Publications Steering Committee 43 Members Data Monitoring Committee Trial Operations Novartis Research Sites 806 centers in 40 countries Endpoint Committees

Primary Objective To evaluate whether valsartan or nateglinide, in addition to lifestyle modification, can reduce the risk of diabetes and cardiovascular events in persons with impaired glucose tolerance (IGT) and either cardiovascular disease or risk factors for cardiovascular disease

Valsartan/Nateglinide (n=2316) Nateglinide/Placebo (n=2329) Valsartan/Placebo (n=2315) Placebo/Placebo (n=2346) NAVIGATOR 2 × 2 Factorial Design All subjects participated in a lifestyle modification program Nateglinide 60 mg three times a day before meals Valsartan 160 mg once a day Nateglinide Comparison Valsartan Comparison

North America 2146 Asia-Pacific 692 Africa 153 Central & South America 1406 Europe 4909 NAVIGATOR Global Enrollment 9306 patients 806 centers 40 countries Major Inclusion Criteria IGT* plus FPG 95 mg/dL (5.3 mmol/L) and either CVD and age 50 yr or 1 risk factor for CVD and age 55 yr *Impaired glucose tolerance according to ADA definition: Nathan DM et al, Diabetes Care, 2007

Coprimary Endpoints Incidence of diabetes FPG 126 mg/dL (7.0 mmol/L) and/or 2 hr PG 200 mg/dL (11.1 mmol/L), confirmed on OGTT within 12 weeks Extended cardiovascular outcome CV death, nonfatal MI, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or unstable angina Core cardiovascular outcome CV death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure

Nateglinide Data

Meal Saloranta C et al. Diabetes Care 2002;25: NAVIGATOR Pilot Study Postprandial glucose lowering with nateglinide in IGT

Baseline Patient Characteristics Holman RR et al, N Engl J Med, 2010 Nateglinide n=4645 Placebo n=4661 Age, years63.7 ± ± 6.9 Female sex, n (%)2368 (51.0)2343 (50.3) Race, n (%) White3854 (83.0)3880 (83.2) Black120 (2.6)116 (2.5) Asian310 (6.7)303 (6.5) Other361 (7.8)362 (7.8) Weight, kg83.6 ± 17.2 BMI, kg/m ± 5.4 Waist circumference, cm101 ± 14 Men104 ± ± 13 Women98 ± 14 Mean sitting BP, mm HG Systolic139.8 ± ± 17.4 Diastolic82.6 ± ± 10.2 History of CVD, n (%)1140 (24.5)1126 (24.2)

Holman RR et al, N Engl J Med, 2010 Baseline Patient Characteristics (continued) Nateglinide n=4645 Placebo n=4661 Glycemic indices Fasting plasma glucose (mmol/L)6.1 ± ± hour plasma glucose (mmol/L)9.2 ± ± 0.94 Glycated hemoglobin (%)5.8 ± ± 0.48 Metabolic syndrome, n (%)3896 (83.9)3898 (83.6) Lipids Total cholesterol, mg/dL210 ± ± 43 HDL, mg/dL50 ± 13 LDL, mg/dL126 ± ± 38 Triglycerides, mg/dL151 (109, 208)150 (107, 209) Creatinine, mg/dL0.9 ± 0.2 Estimated GFR mL/min/1.73m ± ± 19.0 Urinary albumin:creatinine (mg/g)7.1 (4.5, 14.1)7.1 (4.5, 14.8)

Holman RR et al, N Engl J Med, 2010 Adherence to Protocol Taking study drug at 5 years –Nateglinide 70% –Placebo 71% 13% withdrew consent or lost to follow-up, mostly during extension of trial Vital status available for 96% of the possible follow-up time Median follow-up –6.5 years for vital status –5.0 years for incident diabetes

Concomitant Medications Holman RR et al, N Engl J Med, 2010 Nateglinide n=4645 n (%) Placebo n=4661 n (%) P Value ACE inhibitor Baseline330 (7.1)346 (7.4) Last study visit729 (15.7)745 (16.0)0.64 Angiotensin-receptor blocker Baseline12 (0.3)18 (0.4) Last study visit249 (5.4)229 (4.9)0.32 Beta blocker Baseline1872 (40.3)1794 (38.5) Last study visit1913 (41.2)1927 (41.3)0.82 Calcium channel blocker Baseline1519 (32.7)1493 (32.0) Last study visit1674 (36.0)1720 (36.9)0.39 Diuretic Baseline1461 (31.5)1499 (32.2) Last study visit1664 (35.8)1755 (37.7)0.07

Concomitant Medications (continued) Holman RR et al, N Engl J Med, 2010 Nateglinide n=4645 Placebo n=4661 P Value n (%) Lipid-lowering drug Baseline1797 (38.7)1780 (38.2) Last study visit2301 (49.5)2358 (50.6)0.25 Aspirin/other antiplatelet drug Baseline1712 (36.9)1713 (36.8) Last study visit2119 (45.6)2114 (45.4)0.91 Antidiabetic drug Baseline2 (<0.1)5 (0.1) Last study visitall subjects*651 (14.0)670 (14.4)0.61 *For those with diabetes: 33.3% nateglinide, 37.7% placebo

Holman RR et al, N Engl J Med, 2010 Nateglinide Decreased FPG; Increased 2 Hr PG

Holman RR et al, N Engl J Med, 2010 Weight and Waist Circumference Increase with Nateglinide

Holman RR et al, N Engl J Med, 2010 Incidence of Diabetes Placebo1580 events (33.9%) Nateglinide1674 events (36.0%) *Not significant after adjustment for multiple testing

Extended and Core CV Outcomes Holman RR et al, N Engl J Med, 2010 Placebo707 events (15.2%) Nateglinide658 events (14.2%) Placebo387 events (8.3%) Nateglinide365 events (7.9%)

Adverse Events: Hypoglycemia* Nateglinide n=4645 Placebo n=4661 P Value Overall, n (%)911 (19.6)527 (11.3)<0.001 Mild (maximum severity) Moderate (maximum severity) Severe (maximum severity) 2112 Discontinuation for adverse events, n (%) 520 (11.2)485 (10.4)0.23 Holman RR et al, N Engl J Med, 2010 *Includes MedDRA preferred terms: hypoglycemia and hypoglycemic seizure Adverse events otherwise did not differ between treatment groups

Holman RR et al, N Engl J Med, 2010 Nateglinide Conclusions In people with IGT and CV disease or risk factors, nateglinide in addition to lifestyle modification –Did not reduce the incidence of diabetes (median follow-up 5 yrs) –Did not reduce the co-primary CV outcomes

Valsartan Data

Baseline Patient Characteristics CharacteristicValsartan n=4631 Placebo n=4675 Age, years63.7 ± ± 6.8 Female sex, n (%)2317 (50.0)2278 (51.3) Race, n (%) White3849 (83.1)3885 (83.1) Black113 (2.4)123 (2.6) Asian298 (6.4)315 (6.7) Other371 (8.0)352 (7.5) Weight, kg83.5 ± ± 17.1 BMI, kg/m ± ± 5.3 Waist circumference, cm101 ± 14 Men104 ± ± 12 Women98 ± 14 Mean sitting BP, mm Hg Systolic139.4 ± ± 17.1 Diastolic82.5 ± ± 10.1 Any CVD, n (%)1148 (24.8)1118 (23.9) McMurray JJ et al, N Engl J Med, 2010

Baseline Patient Characteristics (continued) CharacteristicValsartan n=4631 Placebo n=4675 Glycemic indices Fasting plasma glucose (mmol/L)6.1 ± hr plasma glucose (mmol/L)9.2 ± 0.9 Glycated hemoglobin (%)5.8 ± 0.5 Metabolic syndrome, n (%)3825 (82.6)3969 (85.0) Lipids Total cholesterol, mg/dL209 ± 42 HDL, mg/dL50 ± 1450 ± 13 LDL, mg/dL127 ± ± 37 Triglycerides, mg/dL177 ± ± 104 Creatinine, mg/dL0.9 ± 0.2 Estimated GFR mL/min/1.73m ± ± 19.0 Urinary albumin:creatinine (mg/g)0.8 McMurray JJ et al, N Engl J Med, 2010

Adherence to Protocol Taking study drug at 5 years –Valsartan 67% –Placebo 66% 13% withdrew consent or lost to follow-up, mostly during extension of trial Vital status available for 96% of the possible follow-up time Median follow-up –6.5 years for vital status –5.0 years for incident diabetes

Concomitant Medications MedicationValsartan n=4631 n (%) Placebo n=4675 n (%) P Value ACE inhibitor Baseline351 (7.6)325 (7.0) Last study visit688 (14.9)786 (16.8)0.005 Angiotensin-receptor blocker Baseline10 (0.2)20 (0.4) Last study visit212 (4.6)266 (5.7)0.02 Beta blocker Baseline1863 (40.2)1803 (38.6) Last study visit1840 (39.7)2000 (42.8)<0.001 Calcium channel blocker Baseline1483 (32.0)1529 (32.7) Last study visit1537 (33.2)1857 (39.7)<0.001 Diuretic, n (%) Baseline1451 (31.3)1509 (32.3) Last study visit1578 (34.1)1841 (39.4)<0.001 McMurray JJ et al, N Engl J Med, 2010

Concomitant Medications (continued) MedicationValsartan n=4631 n (%) Placebo n=4675 n (%) P Value Lipid-lowering drug, n (%) Baseline1782 (38.5)1795 (38.4) Last study visit2298 (49.6)2361 (50.5)0.27 Aspirin/other antiplatelet drug, n (%) Baseline1729 (37.3)1696 (36.3) Last study visit2103 (45.4)2130 (45.6)0.64 Antidiabetic drug, n (%) Baseline1 (<0.1)6 (0.1) Last study visitall subjects*588 (12.7)733 (15.7)<0.001 McMurray JJ et al, N Engl J Med, 2010 *For those with diabetes: 33.4% valsartan, 37.2% placebo

McMurray JJ et al, N Engl J Med, 2010 Valsartan Significantly Reduced Mean Sitting BP

McMurray JJ et al, N Engl J Med, 2010 Valsartan Reduced Fasting and 2 Hr Glucose

McMurray JJ et al, N Engl J Med, 2010 Incidence of Diabetes Placebo1722 events (36.8%) Valsartan1532 events (33.1%)

McMurray JJ et al, N Engl J Med, 2010 Extended and Core CV Outcomes Placebo693 events (14.8%) Valsartan672 events (14.5%) Placebo377 events (8.1%) Valsartan375 events (8.1%)

McMurray JJ et al, N Engl J Med, 2010 Exploratory Outcomes: CV & Total Mortality Placebo327 events (7.0%) Valsartan295 events (6.4%) Placebo116 events (2.5%) Valsartan128 events (2.8%)

McMurray JJ et al, N Engl J Med, 2010 Adverse Events of Interest Valsartan n=4631 n (%) Placebo n=4675 n (%) P Value Hypotension-related*1964 (42.4)1680 (35.9)<0.001 Hypertension693 (15.0)950 (20.3)<0.001 Renal dysfunction136 (2.9)146 (3.1)0.55 Hyperkalemia35 (0.8)35 (0.7)0.99 Hypokalemia45 (1.0)84 (1.8)<0.001 Hypoglycemia731 (15.8)707 (15.1)0.39 Hyperglycemia45 (1.0)44 (0.9)0.93 Angioedema89 (1.9)123 (2.6)0.02 *MedDRA preferred terms include: hypotension, dizziness (including dizziness exertional, dizziness postural), syncope, presyncope and shock (not otherwise specified)

McMurray JJ et al, N Engl J Med, 2010 Valsartan Conclusions In people with IGT and CV disease or risk factors, valsartan in addition to lifestyle modification leads to: –14% relative (3.8% absolute) reduction in the incidence of diabetes (median follow-up 5 yrs) –Did not reduce the co-primary CV outcomes

Thoughts After NAVIGATOR We are in the midst of a global epidemic of obesity, diabetes, and associated cardiovascular disease. Many people with impaired glucose tolerance will develop diabetes in a short period of time, even with standard medical care. Lifestyle intervention remains the cornerstone of diabetes prevention and therapy for impaired glucose tolerance. We must continue to seek better pharmacological treatments while emphasizing exercise and weight control to prevent diabetes and its morbid and mortal consequences. NAVIGATOR demonstrates once again that the risks and benefits of therapies cannot be predicted accurately based on biology and intermediate measures, so they must be empirically demonstrated with proper RCTs

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Disclosures Robert M. Califf, MD reports receiving research grant support from Novartis Pharmaceuticals, Johnson & Johnson/Scios, Lilly, Merck, and Schering Plough, and consulting fees from Annenberg, Aterovax, Bayer/Ortho McNeil, BMS, Boehringer Ingelheim, GSK, WebMd/theheart.org, Johnson and Johnson/Scios, Kowa Research Institute, McKinsey & Company, Medtronic, Merck, Novartis Pharmaceuticals, Sanofi Aventis, and Schering Plough, and an equity position with NITROX, LLC. All personal income from industry relations is donated to non-profit entities. Dr. Califf's industry relations are kept up to date quarterly at

Disclosures Rury R. Holman MD, reports receiving grant support from Asahi Kasei Pharma, Bayer Healthcare, Bayer Schering Pharma, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Merck Serono, Novartis, Novo Nordisk, Pfizer, and Sanofi-Aventis, consulting fees from Amylin, Eli Lilly, GlaxoSmithKline, Merck, and Novartis, and lecture fees from Astella, Bayer, GlaxoSmithKline, King Pharmaceuticals, Eli Lilly, Merck, Merck Serono, Novo Nordisk, Takeda and Sanofi-Aventis.